Methods and compositions for delivery of active agents

Abstract

A lipid particle can include a cationic lipid. Synthesis of the cationic lipid can include a ylide-based reaction, such as a Wittig reaction or sulfur ylide reaction. In some cases, the synthesis can also include a Michael addition or a related addition reaction.

What is claimed is:  
     
       1. A compound of formula IA: 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein 
         X and Y are each, independently, alkyl or aryl; 
         L 1  and L 2  are each, independently, alkylene linking units, which may optionally contain one or more double bonds and further may optionally be interrupted by one or more heteroatoms and/or one or more cycloalkylene groups; 
         R 1  and R 2  are each, independently, C 10 -C 30  aliphatic group, each of which may optionally contain one or more double bonds, and may optionally be interrupted by one or more heteroatoms and/or one or more cycloalkylene groups; 
         Z is —C(O)O—, —OC(O)—, —C(O)N(R 3 )—, —N(R 3 )C(O)—, —O(CO)N(R 3 ), —N(R 3 )C(O)O—, —C(O)N(R 3 )C(O)O—, —OC(O)N(R 3 )C(O)— or —N(R 3 )C(O)N(R 3 )—; 
         each occurrence of R 3  is, independently, H, alkyl or aryl, and 
         --- represents a single bond or a double bond, where when --- represents a single bond, C* is further substituted by hydrogen or alkyl, 
       
       wherein L 2  is a linear alkylene unit and contains one or more double bonds and one or more cycloalkylene groups. 
     
     
       2. The compound of  claim 1 , wherein R 1  and R 2  are each, independently, C 10 -C 30  alkyl or C 10 -C 30  alkenyl. 
     
     
       3. The compound of  claim 2 , wherein one of R 1  and R 2  is a linear C 10 -C 30  alkyl or C 10 -C 30  alkenyl group and the other of R 1  and R 2  is a branched C 10 -C 30  alkyl or C 10 -C 30  alkenyl group. 
     
     
       4. The compound of  claim 1 , wherein Z is —C(O)O—, —C(O)N(R 3 )—, —O(CO)N(R 3 ), —C(O)N(R 3 )C(O)O—, or —N(R 3 )C(O)N(R 3 )—. 
     
     
       5. The compound of  claim 4 , wherein R 3  is H or alkyl. 
     
     
       6. The compound of  claim 1 , wherein
 X and Y are each, independently, C 1 -C 4  alkyl; and 
 each occurrence of R 3  is independently H or C 1 -C 4  alkyl. 
 
     
     
       7. A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and salts thereof. 
       
     
     
       8. The compound of  claim 1 , wherein the compound is in the form of a pharmaceutically acceptable salt. 
     
     
       9. The compound of  claim 1 , wherein the compound is in the form of a cationic lipid. 
     
     
       10. A lipid particle comprising a neutral lipid, a lipid capable of reducing aggregation, and a cationic lipid of  claim 9 . 
     
     
       11. The lipid particle of  claim 10 , wherein the neutral lipid is selected from DSPC, DPPC, POPC, DOPE, or SM; the lipid capable of reducing aggregation is a PEG lipid; and the lipid particle further comprises a sterol. 
     
     
       12. The lipid particle of  claim 10 , wherein the cationic lipid is present in a mole percentage of about 20% and about 60%; the neutral lipid is present in a mole percentage of about 5% to about 25%; the sterol is present in a mole percentage of about 25% to about 55%; and the PEG lipid is PEG-DMA, PEG-DMG, or a combination thereof, and is present in a mole percentage of about 0.5% to about 15%. 
     
     
       13. The lipid particle of  claim 10 , further comprising an active agent. 
     
     
       14. The lipid particle of  claim 13 , wherein the active agent is a nucleic acid selected from a plasmid, an immunostimulatory oligonucleotide, an siRNA, an antisense oligonucleotide, a microRNA, an antagomir, an aptamer, and a ribozyme. 
     
     
       15. A pharmaceutical composition comprising a lipid particle of  claim 13  and a pharmaceutically acceptable carrier. 
     
     
       16. A method of modulating the expression of a target gene in a cell, comprising providing to the cell a lipid particle of  claim 13 . 
     
     
       17. The method of  claim 16 , wherein the active agent is a nucleic acid selected from a plasmid, an immunostimulatory oligonucleotide, an siRNA, an ami sense oligonucleotide, a microRNA, an antagomir, an aptamer, and a ribozyme. 
     
     
       18. A method of inducing an immune response in a subject, comprising providing to the subject the pharmaceutical composition of  claim 15 , wherein the active agent is an immunostimulatory oligonucleotide. 
     
     
       19. The method of  claim 16 , wherein the target gene is selected from the group consisting of Factor VII, Eg5, PCSK9, TPX2, apoB, SAA, TTR, RSV, PDGF beta gene, Erb-B gene, Src gene, CRK gene, GRB2 gene, RAS gene, MEKK gene, JNK gene, RAF gene, Erk1/2 gene, PCNA(p21) gene, MYB gene, JUN gene, FOS gene, BCL-2 gene, Cyclin D gene, VEGF gene, EGFR gene, Cyclin A gene, Cyclin E gene, WNT-1 gene, beta-catenin gene, c-MET gene, PKC gene, NFKB gene, STAT3 gene, survivin gene, Her2/Neu gene, SGRT1 gene, XBP1 gene, topoisomerase I gene, topoisomerase II alpha gene, p73 gene, p21(WAF1/CIP1) gene, p27(KIP1) gene, PPM ID gene, RAS gene, caveolin I gene, MIB I gene, MTAI gene, M68 gene, tumor suppressor genes, and p53 tumor suppressor gene. 
     
     
       20. The method of  claim 19 , wherein the target gene contains one or more mutations.